Polymorphism is the ability of a substance to exist in two or more crystalline forms that have a different arrangement and/or conformation of molecules in a crystalline lattice (see e.g., Chawla and Bansal, CRIPS 2004, 5(1):9-12; Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, 2002, pp. 1-28, 240-256). It has been estimated that a large number of pharmaceuticals exhibit polymorphism. For example, 70% of barbiturates, 60% of sulfonamides, and 23% of steroids are believed to exist in different polymorphic forms or “polymorphs” (Haleblian et al., J Pharm Sci 1975, 64:1269-1288).
In some cases, when crystals of a compound are forming (e.g., crystallizing from a solution), solvent molecules may become entrapped or bound within the crystal lattice. The presence of the entrapped solvent molecules may affect the three-dimensional crystal lattice that eventually crystallizes. The occurrence of a compound (target molecule) crystallizing in different three-dimensional lattices based upon the presence of solvent molecules has been termed “pseudo-polymorphism.” Akin to polymorphs, such “pseudo-polymorphs,” also known as “solvates” (or “hydrates” when the solvent is water), are crystalline solids containing either stoichiometric (i.e., whole number ratios of target molecules to solvent molecules) or non-stoichiometric (i.e., non-whole number ratios of target molecules to solvent molecules) amounts of a solvent incorporated within the crystal structure. In general, different crystalline forms of molecules (e.g., pharmaceutical compounds) can exist in the same or different hydrated or solvated states.
The existence of various polymorphs or pseudo-polymorphs can greatly affect a pharmaceutical's performance since each form can have different physical and chemical properties. For example, one particular polymorph pseudo-polymorph may be more bioavailable, more stable (e.g., longer shelf life), or more easily formulated or tableted than another polymorph. Similarly, one polymorph pseudo-polymorph may be more active or less toxic than another. Some specific examples of the dramatic difference that can exist between various pharmaceutical polymorphs are described in, e.g., Brittain et al., J Pharm Sci 2002, 91:1573-1580 and Morissette et al., Proc Natl Acad Sci USA 2003, 100:2180-2184.
The effects of polymorphism and pseudo-polymorphism on quality and performance of a drug is widely recognized. The exact solid state polymorph (or pseudo-polymorph) of a compound determines its physical properties such as dissolution rate, solubility, bioavailability, crystal habit, mechanical strength, etc. (Datta et al., Nature Reviews—Drug Discovery, 2004, 3:42-57). The delivery of an exact dosage in manufacture and the manufacturing process itself often depend on which of several possible polymorphs or pseudo-polymorphs are present.
The variation in properties among different polymorphs (or pseudo-polymorphs) usually means that one crystalline form is desired or preferred over other forms. Obtaining a particular form can be difficult, however. Typically, researchers have to experiment with a multitude of variables in crystallization conditions, such as aqueous solvent mixtures, amount of water, amount of target compound, relative humidity, temperature of incubation, incubation time, etc., in a process characterized by trial and error. Further, the search for salts of crystalline forms (usually sought after to control dissolution rate and solubility) can require extensive experimentation. Each salt of a drug or each different solvent used to crystallize the drug or a salt of the drug may lead to polymorphs or pseudo-polymorphs that have to be fully investigated and that have different properties (see e.g., Reutzel-Edens et al., “Anhydrates and hydrates of olanzapine: Crystallization, solid-state characterization, and structural relationships,” Crystal Growth & Design, 2003, 3:897-907).
Another common problem that exists with many pharmaceuticals, agrochemicals, nutraceuticals etc. is low solubility. Low solubility can make formulating a particular compound difficult, and generally low solubility translates into low bioavailability. Much research is conducted on finding ways to improve a compound's solubility and availability. Typically methods include complex delivery devices and chemical modifications of the drug.
Polymorphism and pseudo-polymorphism is difficult to predict, i.e., there is a relationship between the crystalline state of a compound and its chemical properties (e.g., dissolution rate, solubility), biological properties (e.g., bioavailability, pharmacokinetics), mechanical and physical properties, and manufacturing processes. In some instances polymorphs and pseudo-polymorphs can interconvert. Moreover, there is a need for compositions that can manifest their base property, for example, their pharmacological properties, while having controllable and/or adjustable chemical, biological, and physical properties, that the formulator can “tune” to the desired properties while at the same time avoiding any undesirable polymorphism. In addition, there is a need for compounds having these properties which have modifiable dissolution and solubility properties. As such, there is further needed methods of preparing and using compositions having these controllable properties. Further, there is a need for methods of converting compounds that are difficult to solubilize into a form that allows for increased solubility. Disclosed herein are compositions and methods that provide for the above compounds, compositions, and methods.